Clinical research into the biology and treatment of acute leukemia is pursued with particular emphasis on acute lymphoblastic leukemia (ALL) of childhood. Major issues being addressed include: 1) development of therapeutic strategies aimed at improving overall prognosis of children with ALL, 2) investigation into the mechanisms of treatment failure with particular emphasis on evaluation of pharmacologic approaches to leukemic therapy, and 3) characterization of adverse sequelae of antileukemic therapy and design of treatment regimens which avoid them. The major ALL treatment protocol has successfully demonstrated that high-dose, protracted systemic methotrexate infusions can substitute for cranial radiation as central nervous system (CNS) preventive therapy for the majority of patients with ALL. Moreover, analysis of data derived from this study had identified a patient group at particular risk for CNS relapse. A new, high risk protocol has been devised in an attempt to improve the prognosis for these and other poor risk patients. Studies on the bioavailability of orally administered maintenance chemotherapy have demonstrated that many patients do not achieve adequate drug levels in the blood, raising concern over this possible mechanism of treatment failure. A major, multi-institutional pharmacologic monitoring protocol has been instituted in an attempt to study the relationship between the bioavailability of orally administered maintenance chemotherapy and relapse in children with ALL. The role of diurnal variation, concomitant food intake and inter-patient variability in intracellular drug metabolism are being explored as possible factors in treament failure. Studies on late effects have demonstrated CT brain scan, neuroendocrine, and psychometric test abnormalities in long-term survivors of childhood ALL. These observations have stimulated the search for alternative, equally effective but less toxic methods of CNS preventive therapy.